Monday, July 12, 2010

BREAKING NEWS: PAGOCLONE NOT SUCCESSFUL.

Endo Pharmaceuticals has completed the initial analyses of the data from an ongoing pagoclone study (IP456-041). Although the study did not meet its pre-specified criteria for success, there were some trends of interest that Endo will look at more closely by conducting additional analyses of the data. The last part of this study will continue until completion late this year. A second active pagoclone study (IP456-039) will be closed in an orderly manner over the next several months. Patients participating in that study will be encouraged to discuss other treatment options with their physicians.

Endo's statement is in line with my predictions. Pagoclone did not meet the pre-specified criteria for success. Re-phrased for common people: Pagoclone was not successful. ;-) Each trial needs to set a hurdle for success before the trial to avoid shifting the definition of success after data analysis. And the open-label trial of Phase IIa is closing, but the other one is running until the end of the year. They write that "trends of interest that Endo will look at more closely by conducting additional analyses of the data". There are two interpretations, both not mutually exclusive. First, every good PR will add some positive spin or anchor of hope to soften the blow of negative news. We humans need hope when our dreams are hit. They also want to smooth out any hit on their stock price, which has not yet seen a hit by the news. Interestingly, the stock price has been very stable: see graph. Given that the revenues for Pagoclone are now much more likely to be zero, reducing the company's future cashflows and thereby reducing the company value and its equity part. If you have stocks, sell. Or short the stock, sell a future, go long a put or short a call. Second, I would not be surprised if there were pockets of real hopes, i.e. deviations in the data. Some might have responded well while others didn't.The question remains then whether there is a sub-type reacting to Pagoclone. My gut feeling is probably. Maybe for those that are borderline anxiety/panic disorder, which in combination with a low capacity speech system develop significant symptoms. But that's pure and total speculation on my part. A rigorous statistical analysis combined with deep understanding of the nature of stuttering and its traps is needed.

To be crystal clear: Pagoclone is not the wonder drug for everyone many hoped for. At the very best, Pagoclone might be able to modulate the fluency of a sub-type of stutterers. I am sorry to tell you. You will all hate me for spreading the bad news, right? ;-) Tom is just so skeptical and negative. But listen it is not my fault. I am just telling you about reality. I am not creating or causing it!

37 comments:

Anonymous
said...

well, you can't expect from virtual condition like stuttering to have unvirtual pill (read placebo). Stuttering is something that happens when you talk with others.. When you're alone you don't stutter, so you don't need a pill. When you speak with others you need something that will fool the brain to act like when you are alone. Placebo is a good method for the brain to be cheated. So, maybe the Pagoclone results do not differ from placebo, but that is not a reason not to be released.

And for the claiming that everybody can overcome stuttering. Yes, if they spent 5 years in intensive breathing-relaxation-socialization treatment. Been there , done that. For last 3 years my stuttering is reduced for about 99%. But, you have to have A LOT of time, frustration, failing and importunity first.

Pagoclone has definite, obvious results for me. Everyone in my family could tell. My wife could tell if I missed a dose in the morning. Most importantly, *I* could tell. Placebo effect could not account for the huge and sudden increase in fluency that I attained while on Pagoclone, nor would it cause the sudden drop in fluency when I forget to take them. The effect is too large and too regular.

Maybe it didn't work as well for other people. But given the fact that they've had the drug in an open label trial for 3+ years past the double blind study - seems to indicate they found something worth continuing the study.

placebo can be significant especially when you and your family come to expect a relationship.

You must also consider that by chance your fluency patches might correlate to when you were on Pagoclone. Yes, the probability is small, but multiply this by 100 and the profitability is not that small. It's like lottery winners. The chance that you win is very small, but if a million people play it is actually big.

Andrew, the drug failed the test and will NOT be available in its current form.As for Finch’s success, there is a chance as Tom speculates that he falls into a sub type that is helped but I think it’s a lot more likely that he is helped through a placebo effect which has been very well documented with all kinds of other serious health problems.I’d think that in stuttering the placebo effect is even stronger, every therapist knows (or should know) that new patients often develop a “false fluency” just by attending therapy and trying to help themselves. Furthermore, the placebo effect is very well documented with Parkinsins disease which as suggested with stuttering is affected by dopamine levels.I’m sorry to hear that the pill won’t be but not surprised and I’m sorry to say, not that upset about.I think a ‘pill’ could help some but I also believe that it would not help others. Many PWS develop many destructively self limiting cognitive distortions (such as avoidance behaviors) which will not magically go away with the stuttering. These distortions are experience based and bread and once there will take on a life of their own.Even if a pill can cure the brain of stuttering, it will do nothing for the mind.One thing I’ve learned is that even if I incredibly and miraculously woke up tomorrow stutter free with the knowledge that it was gone for good; I’d still have the mind of a stutterer.

Mr. Finch is not alone. There's been a lot of talk about the placebo effect on this forum, but I join the ranks of Mr. Finch and others who have found success on this pill. I also have the same story as Mr. Finch. On = FluencyOff = Disfluency...EVERY TIME.EVERY SINGLE TIME. It even proved itself in the double blind portion of the study. I was on, then off, and then back on again. However, when I was off of pagoclone and on a placebo, my stuttering was terrible. But I had no way to know whether I was on or off. For me, Pagoclone works, plain and simple.

Tom - you wrote: "Given that the revenues for Pagoclone are now much more likely to be zero, reducing the company's future cashflows and thereby reducing the company value and its equity part. If you have stocks, sell. Or short the stock, sell a future, go long a put or short a call."

I need to quibble with your advice. Markets react very quickly. This news is already public, and the markets have already processed the news and adjusted the price accordingly. Your advice would be effective only if someone had inside information which hadn't yet been publicized. (Of course, in the US it's illegal to trade on inside information.) After any news has become public, it's too late.

This is a company with a market capitalization of $2.73 billion and revenues of $1.5 billion. I suspect that the market in this stock is dominated by large, institutional investors. Professional traders and analysts pay close attention to the stocks they watch, and closely monitor sources of information, particularly a company's website.

Once they traders see the change on the company website, they'll find your blog in 10 seconds by a Google search on "pagoclone".

"No the news is not public in the sense of a press release. I have found the statement on their website and they did not spread it out. So only a very limited number of people knew about it." - That limited number of people undoubtedly includes the professional traders who dominate trading in these stocks.

It's hard to imagine that any material information is not processed very quickly by the market for a company as big as that. It may not happen within five minutes, but certainly within a few hours.

The fact that the stock has not moved much is more likely to reflect the the fact that the value that the professional investors have placed on the pagoclone income stream, risk adjusted, is comparatively small.

I agree with your point on mosaic theory (although your speculations, and your references, to Maguire's talk are readily available to anyone who Googles the word "pagoclone").

1. Your guess of $1000/year is probably a reasonable guess. However, patent protection is normally available only for 7 years. After that, generics become available from other companies, so that the sales from the original manufacturer drop off, and the price is lowered.

2. 100,000 seems too high to me. But who knows???

3. Based on preliminary reports, the effectiveness of the drug is limited. This probably limits the sales.

4. I'd guess the market prices in a probability value of less than 50%. Most experimental drugs don't make it to market. Also, if the effectiveness of the drug is limited, this also reduces the probability that the drug will ever be brought to market.

For reasons 1, 2, and 3, I would reduce your estimate of the present value of sales by about 75%. And for reason 4, I would reduce your 50% to 25%. That reduces your risk-adjusted $500 million to about $60 million, or about 2 of the company's market value. Even so, this would translate to a stock price drop of $0.50. Any you're right, we haven't seen it.

I still believe the market reacts very quickly to a development like this, so maybe the market valuation of the pagoclone income stream (risk adjusted) is less than our estimates. Or maybe you're right that it just takes awhile.

Anyway, it will be interesting to see what happens to the market price in the next few days.

I can not debate chemistry with you as you are the obvious subject matter expert but I do appreciate the "genius" recognition. I also can not rule out the placebo effect 100%. However, from my experience while going through the study completely and learning, after the fact, when I was on and off pagoclone, and knowing my pre-therapy levels of disfluency, pagoclone levels of disfluency, sugar pill levels of disfluency and then pagoclone levels of disfluency, etc. etc. I feel very confident in saying, that it works. It not only works, but on the higher dosage, it worked better. How much did it work? How much did the placebo effect have? I guess we will never know. Thanks as always for your continued dedication to this affliction we all have. I think you can sum up all of the attention pagoclone received over the last couple of days with a tremendous let down from the stuttering community. There was a lot of hope wrapped up in this pill. People just want relief from their frustration, embarassment and feelings of despair concerning their condition. Can't blame them for that.

The bad news is that Pagoclone is forever looking for a disease to treat. It surprised me that it didn't work out for panic attacks because it definitely relaxes the mind. I hope they don't give up but consider mixing pagoclone with something else to form a more effective drug for stutters.One such drug that might work well with pagoclone is a beta blockers. I'm sure there are many other possibilities.

I am in the Pagoclone study and stutter severely. Here is my experience: Pagoclone does has some effect on my stuttering but not as much as I had hoped. It definitely has an effect on ameliorating my vocal cord tension. I believe this is a real effect and not a placebo effect. However, being on the drug made me realize that my stuttering was more of a multifaceted problem than I thought. There is a tendency to think of stuttering as being caused by only by locking of the vocal cords. But although my vocal cords felt more relaxed while on Pagoclone, I still had problems with what I would describe as the mouth aspects of stuttering. The pagoclone made me realize that in addition to my vocal chords locking up, my mouth was kind of uncoordinated when it came to word formation and that this contributes a great deal to my stuttering problem. Pagoclone did not effect this aspect of stuttering for me. And I would say that although you hear a lot about how Pagoclone is free of side effects, for me there were very subtle but negative psychological effects to being on the drug for over a year.

>> I feel very confident in saying, that it works. It not only works, but on the higher dosage, it worked better. How much did it work? How much did the placebo effect have? I guess we will never know.

How do you know? In the blind study you cannot know. So you must be talking about the open label phase. Were you able to change dose?

Tom,Yes, able to up the dosage in the open label phase to the highest dose. I was really looking forward to increasing the dosage even more to see what the effects were. I suppose that I can do that on my own, but since I only have a few pills left, don't want to waste any on experimentation.

HelloI am a stammerer with no chemestry or specialist knowledge to do with this, so i want to make it clear in my own mind and possible convince myself of some hope.Would it be possible or even likely that the drug is effective in treating stammering but fails the trial in some other area? eg side effects or likely abuse, any other criterea that could not be sorted before the end of the trial. Tony

Here's an article from today's NY Times about the way drug companies hide negative results - http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?hp

"In the fall of 1999, the drug giant SmithKline Beecham secretly began a study to find out if its diabetes medicine, Avandia, was safer for the heart than a competing pill, Actos, made by Takeda....But the study’s results, completed that same year, were disastrous....But instead of publishing the results, the company spent the next 11 years trying to cover them up."

If Endo Pharmaceuticals kills pagoclone, it doesn't matter what they publish. But if they decide to proceed with development of the drug, I wonder what they'll do with their test results - what they'll publicize and what they'll hide.

Well, sorry for all the people who have tried and hoped ... but one good thing about capitalism is that it always tries to reduce costs. It's the humans who cannot look further and give it an ugly face sometimes ...After a long journey from Pfizer to Indevus and now Endo (sorry, in case I confused some companies' names) it was now time to really have a look on what Pagoclone can do. For me it could have never really change people's mind about what stuttering actually is and can be. It is a plain scientific approach and therefore it is good that the hope to make money with it was conquered by its own origins.

And, as Ora already mentioned, the tests for premature ejaculations ... when I heard/read bout that it made me laugh out loud some years ago ... and still does so.

So, R.I.P. Pagoclone ... I had a good time with you though I have never met you personally :)

Read the notice carefull. It's clear thAT Fsomething has happened . . . Endo Pharmaceuticals has received the results of the large test, and they're not happy because they did not reach their goas. It does seem clear that they were unhappy with the results, which failed to meet their defined targets.

But that does NOT mean that they're droppping the drug. They have spoken of "trends of interest that endo will look more closely [at] by conducting additional analyses of the data. The study will continue until completion. It is not being closed down immediately.

They've also closed down the earlier, smaller study. This does not necessarily mean bad results; it can also mean that they've found out what the wanted to.

While this the substance and the tone of the announcement are is clearly not positive, it also doesn't mean they're killing the drug now.

Although I'm not optimistic, if we examine their statement at their word, it does not present a hopeless picture, It's quite possible that there are some sub-types of the stuttering population who ARE helped, as Tom suggested.

The pagoclone studies have been ongoing for a long time, and we'ree all impatient, and I think we'd all prefer to have a definitive outcome now: either pagoclone has succeded, or it's dead and they're dropping it. It's always emotionally comforting to have a definite outcome, even if it's negative. But as I read the reports, the situtation is murky, but not hopeless. The tests have not been fully stopped. (Maybe they discontinued the initial study -039) simply because they've learned all they can from it.)

It's clear that we don't have much information, but it's also clear that they have not simply "pulled the plug" on everything, as they might have.

Let's wait and see what happens.

It's too early to have a requiem nass for pagoclone - Requiescat in pace. Pagoclone is still alive. Last week my attitude about pagoclone was impatient but optimistic. Today it's still hopeful, though skeptical and less optimistic. But I think it's premature to despair.

>Pagoclone should continued to be researched for its effectiveness in reducing premature ejaculation.>The SFA and its goal for providing Gene replacement therapy to all those who stutter should completely be developed soon. That's a good one ;) ... though I am not a very big fan of black humour

@OraFor me Pagoclone was a "stillbirth" from the very beginning, since I do not believe that a pill or any other medication will essentially help in case of stuttering. I had some discussions - here in Germany - about that some years ago. After a while I stopped to read all these hopes and this and that ... it's more useful to use your time in dealing with it.I mean I have met women who said they would find stuttering sexy (whatever that meant - no clear idea :)) or said "I love it." (no idea if this was serious) .. but who cares ... in the end it is all about accepting it as a part of you ... and once you learn that it can be a treasure ...

Besides, have you ever heard of someone who could cure his depressions by using an anti depressiva???So, why waiting for a "stutter pill"?

"Besides, have you ever heard of someone who could cure his depressions by using an anti depressiva???So, why waiting for a "stutter pill"?"

Well, yes, plenty of people. Haven't you?

Antidepressants are widely used and widely effective. There are well-known problems in that sometimes it's necessary to try more than one to find one that works. But in general, the effectiveness of antidepressants has been well established, for decades.

There have also been statistically valid studies showing some effectiveness for drugs against stuttering (such as risperdal, olanzapine, ziprasidone, pagoclone). Why would you think otherwise?

@OraAs far as my experiences reach people who took antidepressants got sort of tranquilized. If that is what people what then okay "Mission accomplished". If this is what people were looking for, okay, here we go.A free life looks different for me.It is about growing with oneself's stuttering.But eventually, it comes down to a question of the definition of what the essential, actual problem is people have with their stuttering.

But hey, I don't mind if someone tries to do research on THE stutter pill.

Besides, "valid drugs" ... I sometimes smoke a hand-rolled cigarette with no additives (at least if I believe the tobacco company) to relax and yes, it can be effective "against stuttering" or moreover for "more fluency in speech" for me ... but no-one (incl. myself) would seriously try to make a rule out of that as they try with drugs.

In the end, you exchange one addiction (of being perfect ... what ever that is) with another one (taking drugs) plus keeping the old one if you are unlucky.

Pagoclone 100% worked for me. And I can 100% tell you that it was not a placebo effect. I became so fluent that most people I encountered had no idea I stuttered, and speaking became so effortless for me that at times I even forgot I have a speech impediment. Going in I had exactly zero hope Pagoclone would work for me. When it did I was amazed and giddy. My fluency was never 100% perfect, but it was close. And every word came easier.

Having participated in the study for the past four years, I have to seriously question how the trial was run and what kind of data was gathered. I have been in the maintenance phase of the trial for the past 2 or 3 years. During that trial, no meaningful data was gathered. And when meaningful data was gathered, the tests were hardly rigorous, and consisted of reading a prepared paragraph while being recorded. I only had to read one paragraph, and that only lasted a few minutes. I work for a drug company and am very familiar with the clinical trial. Honestly, there is a lot more the drug company could have done to prove Pagoclone's efficacy. All of us are being done a huge diservice by not being allowed to take Pagoclone. That little white pill totally and completely changed my life. And now my Pagoclone is gone. And I am shattered.

I was on the trial here in Denver from approx March/April 2009 to November of 2010. From April 2009 to approx December 2009, I was on the placebo pill. In December 2009, I started taking the 1.20/day ( which was the max). Fairly quickly my fluency started to increase and speaking was hardly an issue. ( meaning I RARELY stuttered). I'd go out on dates, I was perfectly fluent. I'd see OLD friends that was used to me stuttering fairly bad, they were shocked to see the difference, to see me being so fluent.

Unfortunately the trial for me ended in November of 2010, and even though I KNEW Pagoclone worked, you don't realize HOW MUCH it worked until you get off Pagoclone. I've been off of Pagoclone for approx 7-8 weeks and I can't remember stuttering this bad, it's been so long. One of my biggest things I noticed was I usually had a difficult time speaking over the phone with people I didn't know, and right before the end of the trial I had a few phone interviews that I was nearly 100% fluent on. Now, speaking on the phone to people I don't know, I'm terrible at it.

All in all, I'd be disappointed if Pagoclone wasn't on the market some day.

About 19.4% reduction in percentage of syllables stuttered respect to placebo is not rubbish. And the review is Feb2010.This means that something change and so the drug can be chemically optimized.However do remind that stuttering is a personal characteristic instead of a pathology. A pharmacologic treatment could be useful only during speaking reabilitation, not as a long-life drug.

This "poor" outcome may be a very typical example of the current methodoloy in drug testing. In the last decades it has become increasingly evident that almost every disease can be "stratified" into a large number of sub-classes.

I.e. what is being diagnosed as "prostate cancer" or "breast cancer" actually has a highly diverse range of "root causes".

Details on this are complicated, however, the key word is "patient stratification"

Language too is a phenomenon in which many neural and muscular functions must precisely act together. Thus, it may be very likely that also stuttering can be caused by many different problems.

Another thing being realized now is that drug efficacy is a biomarker in inself: Prostate cancer patiens responding to a certaindrug probably share the same root cause for the cancer! Those patients may, however, account for only 10-20% of all the patients diagnosed as prostate cancer patients by a doctor.

Consequently, in such a trial, the drug would be not approved/marketed because no significant effect could be established EVEN THOUGH 20% OF THE PATIENT WOULD ACTUALLY BENEFIT!!!

I think we have exactly such a situation with Pagoclone!!! Big Pharma is only slowly realizing the importance of disease stratification.

I participated in the pagaclone trial prior to 2005. I have tried to participate again since. The drug worked very well for me eliminating panic attacks. I could no longer present in front of 4 or 5 people and fortunatley for me i was in the trial when we had a meeting with 50 to 100 people and i found myself standing up and speaking freely without the physical reactions i had before. Beta blockers and diazepam do work, but rebounds from them are horrible. The only negative respone i had from the trial was i had a severe chest pain a week in as if it changed my heart rythym. Then a week after i stopped taking it the same chest pain. I have since been taking GABA and diphenhydramine at night to knock me down for the night and keep me calm for the day. I say bring on the pagaclone. Dan

To Dr. Weidig:First of all, I should mention that regardless of the economic considerations you've drawn and based on what you cited from Endo website about the first and second studies of pagoclone, this does not mean that pagoclone is not completely a failure. It might have be seen that other study or trend had covered more positive results cases, etc. I am myself a partial stammerer. I am watching my disorder over 3 years thoroughly and I have come on conclusion that my disorder is completely related to something in my brain, not spiritual psychological issues. please define "might be able to modulate the fluency of a sub-type of stutterers".

"Pagoclone 100% worked for me. And I can 100% tell you that it was not a placebo effect"

That's what they all say. That fact that you attempt any judgement at 100% certainty shows that you either don't understand the concept of the placebo effect, or you think a person like you is not subject to an effect that is 'all in the mind' out of vanity.

Double blind studies are done precisely to account for people like you, who are SURE you know. You don't.

Or perhaps he does understand the concept of the placebo effect but the effect is so different that he CAN tell? I myself have been a stutterer for years now. Nothing I have done has completely erased it. My point is, stuttering and not stuttering are very differentiable. I am fairly sure if he says it worked, it DID work for him. People know themselves better than anyone else, generally speaking. Instead of calling him vain or implying stupidity, why don't you consider what he's saying more thoroughly?